Why Vasculitis Probably can be Ameliorated with Magnesium and Antagonists of Ceramides and Platelet-Activating Factor Volume 3 - Issue 1

Burton M Altura^1-7*, Asefa Gebrewold^1,6, Anthony Carella¹, Nilank C Shah¹, Gatha J Shah¹, Lawrence M Resnick⁸ and Bella T Altura^1,3-7

• ¹Department of Physiology and Pharmacology, SUNY Downstate Medical Center, New York, USA
• ²Deparment of Medicine, SUNY Downstate Medical Center, New York, USA
• ³The Center for Cardiovascular and Muscle Research, SUNY Downstate Medical Center, New York, USA
• ⁴The School for Graduate Studies in Molecular and Cellular Science, The State University of New York Downstate Medical Center, Brooklyn, New York, USA
• ⁵Bio-Defense Systems, Inc, Rockville Centre, New York, USA
• ⁶Orient Biomedical Inc., Estero, Florida, USA
• ⁷Magnesium for Health Foundation, Patterson, California, USA
• ⁸Department of Medicine, Cornell University College of Medicine, New York, USA

Received:June 24, 2019;   Published: July 02, 2019;

Corresponding author:BM Altura, Department of Physiology and Pharmacology, SUNY Downstate Medical Center, New York, USA

DOI: 10.32474/SCSOAJ.2019.03.000153

Abstract PDF

Introduction

Vasculitis is characterized as an inflammatory disease of the body’s small blood vessels, particularly in the lungs and kidneys [1-4]. Many other organ regions are usually affected which often induces morbidity and mortality [1-4]. Although the exact causes of vasculitis are not known, it appears to be an autoimmune disease even though physical, chemical injuries and infections can result in vasculitis [1-4]. It is classified as a rare disease in the USA because there are only about 200,000 cases. Although numerous treatments have been advocated, there is no known cure or preventative treatment. Vasculitis often leads to difficulties in breathing and renal shut -down. In addition, vasculitis leads to cardiac malfunctions, cardiac failure and strokes. Vasculitis is clearly more common in the aged [1-4]. Recently, we have found that a few patients that were diagnosed with vasculitis appear to have a magnesium deficiency (MgD), particularly in the serum ionized Mg²⁺fraction [unpublished findings].

Unlike atherosclerosis that takes decades to develop, vasculitis of small and medium sized arterial vessels, as well as microscopic arterioles. venules and capillaries, progresses rapidly, thus producing tissue ischemia via lumen-occlusive intimal hyperplasia and inflammatory syndromes [1-4]. Whether the end result is giant cell arteritis (GCA), polyarteritis nodosa (PAN), Churg- Strauss vasculitis (CSV), Wegner granulomatosis (WG), polymyalgia rheumatica (PR), Behcets disease (BD), or other vascular diseases, invasion of the arterial and microcirculatory walls by macrophages, leukocytes and CD4 T-cells seems to be pivotal [1-4]. In addition, most of these patients appear to demonstrate coagulationopathies. The degrees of luminal stenoses vary from patient to patient. Usually, degradation of the internal elastic laminae (EL) follow suit [1-3]. It has been hypothesized that the latter stenoses are due to concentric growth of the intima which seems to be related to several angiogenic growth factors, e.g., platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) [4]. What stimulates the production of these growth factors is not completely known but is thought to involve activation of nuclear-factor-KB (NF-kB) in the macrophages and leukocytes [4]. As stated, the macrophages and leukocytes clearly play key roles in the development of vasculitis. They are activated by NF-kB to produce a host of cytokines and chemokines which are needed for tissue remodeling and granuloma formation in development of vasculitis [2,4]. What activates the macrophages and leukocytes to induce production of NF-kB is not known.

Why Magnesium Deficiency is Most Likely a Key Player in Development of Vasculitis

While we were routinely investigating the potential role of magnesium deficiency (MgD) in numerous cardiovascular- diseased patients, who presented with coronary arterial diseases, coronary vasospasm, acute myocardial infarctions (AMIs), congestive heart failure , and strokes, we noted that several of these patients had an underlying vasculitis together with significant deficits in serum ionized Mg, but not necessarily total serum Mg levels [5]. More than 50 years ago, two of us found that reduction in the concentration of extracellular free Mg ions (Mg²⁺ ) resulted in vasospasm of coronary, cerebral, and peripheral arterial vessels; the lower the [Mg²⁺ ]0, the more the intense the arterial vasospasm [6-13]. In addition, our laboratories found that microscopic blood vessels in skeletal, cutaneous, and cerebral vascular beds of intact rats, mice, rabbits, guinea- pigs, dogs, and piglets exhibited similar phenomena as dietary Mg intake was reduced over three to 12weeks [14,15]. Moreover, vascular reactivity to circulating humoral and hormonal vasoconstrictor agents (i.e., angiotensin II, norepinephrine, serotonin, numerous peptide mediators, etc.) was intensified when [Mg²⁺ ]0 was reduced; the lower the [Mg²⁺ ]0 , the greater the humoral and hormonal-induced vasoconstriction [6-10,13]. It is important to note, here, that these agents are often present at increased, circulating levels in cases of vasculitis. It is now clear that all cases of vasculitis are associated with increased levels of various cytokines and chemokines (e.g., IFN-alpha, IL-1-beta, IL-2, IL-8, IL-10, IL-4, IL-17, TNF-alpha, MCP-1, among others) which are pro-inflammatory in nature [1-4]. We have found that rats placed on MgD diets for 21days generate all of these pro-inflammatory cytokines and chemokines in the blood, cardiac tissues and arterial vessels [16,17]. Other investigators have also reported finding many of these cytokines and chemokines in MgD animals [18]. Furthermore, we have found that. These MgD animals generate growth factors similar to those found in patients presenting with various forms of vasculitis [4,5]. All of these cytokines, chemokines, and growth factors, we found in the MgD animals, were associated with microvascular wall remodeling and pathological alterations in the postcapillary venules, resulting in reduced lumen sizes, increased vascular reactivity, and adherence of leukocytes and macrophages on the endothelial cell walls [19-21], thus, in many respects, similar to what is seen in vasculitis. Last, but not least, we have found that the MgD state that we produced in the rats resulted in activation of NF-kB in cardiac, cerebral, and peripheral vascular smooth muscle cells [16-23]. In view of our findings, we believe, collectively, it is difficult to dismiss the probable role of MgD in the etiology and sustenance of a state of inflammation and vasculitis. Thus, we recommend that our hypothesis should be tested in two ways [24-26]:

a) Use a Mg²⁺ -ion selective electrode like those we helped to pioneer [27-31], in order to carefully measure the levels of ionized free Mg; and

b) Administer Mg salts, initially, intravenously, then orally, for extended periods of time.

Low Mg²⁺ Induces Leukocyte and Macrophage Sticking, Increased Adhesiveness to Venular Endothelial Walls, and Increased Post-Capillary Permeability in The Microcirculation

Approximately 40 years ago, Ross et al advanced the hypothesis that atherosclerosis is an inflammatory disease brought about by injury to the endothelial surfaces of the macro- and microcirculations [32]. The hypothesis stated that different forms of injury (e.g., ischemic events) will result in numerous dysfunctions in the homeostatic properties of the endothelium, e.g., increases in adhesiveness of macrophages and leukocytes and/or platelets, alteration in the procoagulant properties, formation/release of cytokines/chemokines and growth factors. Usually, inflammation is defined as a response of microcirculatory blood vessels and the tissues they perfuse to infections and damaged tissues which bring cells and host-defense factors/molecules directly from the circulation to all the diverse sites where they are required in order to eliminate/degrade the offending agents [33]. The mediators of the defense mechanisms include white blood cells, macrophages, phagocytic leukocytes, chemokines, antibodies, and complement proteins [33]. The inflammatory process brings these cells and molecules to the damaged or necrotic tissues. During the normal inflammatory process, macrophages, leukocytes, and monocytes migrate across the venous capillary walls through holes in between the endothelial cells due to increases in permeability and move to the site(s) of injury via chemotaxis. This sequence of events is thought to take place in all types of inflammatory events and in developing vasculitis [34]. The normal mediators for these processes to take place are adhesion molecules, cytokines, and chemokines, all of which we have found in patients with different forms of vasculitis and in MgD [5,23].

Probable Contributing Roles of Ceramides and Platelet- Activating Factor as a Consequence of MgD to Etiology of Vasculitis

In the late 1990’s, working with proton-nuclear magnetic resonance spectroscopy (1H-NMRS), and arterial vessels exposed to low Mg²⁺ levels, two of us found an increased synthesis of several sphingolipids (namely, ceramides, sphingosine, and sphingosine-1- phosphate) along with an increased formation of platelet-activating factor (PAF) [35,36]. We and others have reported that many of these sphingolipids (particularly ceramides) and PAF promote vasoconstriction and vasospasm of different types of arterial blood vessels as well as arterioles and muscular venules in the living microcirculation in situ [22-24,26,37-41]. In addition, three of us found that ceramides and PAF cause increases in postcapillary permeability, leukocyte and macrophage adhesion to the endothelial linings of the postcapillary venules, and migration of these latter cell types to the extravascular tissue spaces [41]. What we found, of particular interest, is that vascular smooth muscle cells (of different types), when exposed, in primary cell culture, to low Mg²⁺ caused a synthesis of both ceramides and PAF, which could be selectively inhibited using specific antagonists of ceramides and PAF [42]. More than 30 years ago, Cunningham and colleagues reported that sera from rheumatoid vasculitis patients contained platelet-releasing activity [43]. Two years later, Warren and his colleagues, using a rat model of immune complex vasculitis, found that a receptor blocker of PAF inhibited an Arthus reaction [44]. Sera taken from patients in our hospitals which had an underling vasculitis (of diverse origins), and lowered serum ionized Mg, demonstrated increased levels of both ceramides and PAF [5]. We do not believe these findings are merely coincidental. It is our contention that low Mg coupled to increased cellular and serum levels of ceramides and PAF are causal agents in many types of vasculitis.

Conclusion

Although the exact cause(s) of vasculitis is not known, Mg depletion appears to be a presence in different types of vasculitis. When several of our cardiovascular- diseased patients were admitted to our hospitals, a number of them exhibited an underlying vasculitis coupled with an ionized Mg deficiency along with elevated serum levels of ceramides and PAF. Mg-deficient animals, in our labs, exhibited elevated serum and tissue levels of ceramides and PAF which could be reduced/inhibited with specific antagonists of ceramide and PAF synthesis. Elevated dietary levels of Mg also reduced the synthesis of both ceramides and PAF, at least in experimental animals. Experimental animals fed Mg deficient diets exhibited, in-vivo, inflammatory alterations in the microcirculation similar to those patients presenting with different forms of vasculitis (e.g., elevated cytokines, elevated chemokines, elevated adhesion molecules, elevated tissue levels of NF-kB, along with other substances). In view of these new findings from our laboratories, it is our belief that patients exhibiting vasculitis should be treated with oral Mg supplements along with inhibitors of ceramide and PAF synthesis in order to determine if our hypothesis is valid.

Acknowledgement

Much of our original investigations were supported, in part, by research grants from The National Heart, Lung and Blood Institute, The National Mental Health Institute, The National Institute on Drug Abuse, and The National Institute on Alcoholism and Alcohol Abuse along with unrestricted research grants from several pharmaceutical companies. Some of our studies were initiated while two of us (BMA and BTA) were on the faculty of The Albert Einstein College of Medicine. While our original studies were underway, two of our colleagues passed away, namely Professor Lawrence M. Resnick and Anthony Carella. Both of these outstanding scientists will be sorely missed.

Acknowledgement

Much of our original investigations were supported, in part, by research grants from The National Heart, Lung and Blood Institute, The National Mental Health Institute, The National Institute on Drug Abuse, and The National Institute on Alcoholism and Alcohol Abuse along with unrestricted research grants from several pharmaceutical companies. Some of our studies were initiated while two of us (BMA and BTA) were on the faculty of The Albert Einstein College of Medicine. While our original studies were underway, two of our colleagues passed away, namely Professor Lawrence M. Resnick and Anthony Carella. Both of these outstanding scientists will be sorely missed.

References

1. Amezcua Guerra LM (2011) Advances in the Etiology, Pathogenesis and Pathology of Vasculitis. In Tech, Croatia.
2. Kumar V, Abbas AK, Aster JC (2015) Blood Vessels In: Robbins and Cotran Pathologic Basis of Disease, 9^th Elsevier Saunders, New York, pp. 505-513.
3. Sharma A (2015) ed Textbook of Systemic Vasculitis. Jaypee The Health Science Publisher, New Delhi, India.
4. Djordjevic VB, Cosic V, Zvezdanovic-Celebic L, Djordjevic VV, Vlahovic P (2011) Endothelial cells and vasculitis. In: Advances in the Etiology, Pathogenesis and Pathology of Vasculitis. In Tech, Craotia, pp. 153-178.
5. Altura BM, Resnick LM, Carella A, Altura BT (2019) Ionized hypomagnesemia in patients with diverse forms of vasculitis. Submitted.
6. Altura BM, Altura BT (1971) Influence of magnesium on drug-induced contractions and ion content in rabbit aorta. Am J Physiol 220: 938-944.
7. Altura BM, Altura BT (1974) Magnesium and contraction of arterial smooth muscle. Microvasc Res 7: 145-155.
8. Altura BM, Altura BT (1978) Magnesium and vascular tone and reactivity. Blood Vessels 15: 5-16.
9. Altura BM (1979) Sudden-death ischemic heart disease and dietary magnesium intake: Is the target coronary vascular smooth muscle? Med Hypoth 5: 843-849.
10. Turlapaty PDMV, Altura BM (1980) Magnesium deficiency produces spasms of coronary arteries: Relationship to etiology of sudden death ischemic heart disease. Science 208: 198-200.
11. Altura BT, Altura BM (1980) Withdrawal of magnesium causes vasospasm while elevated magnesium produces relaxation of tone in cerebral arteries. Neurosci Lett 20: 323-327.
12. Altura BM, Altura BT (1981) Magnesium ions and contraction of vascular smooth muscles: Relationship to some vascular diseases. Federation Proc 40: 2672-2679.
13. Turlapaty PDMV, Weiner R, Altura BM (1981) Interactions of magnesium and verapamil on tone and contractility of vascular smooth muscle. Eur J Pharmacol 74: 263-272.
14. Altura BM, Altura BT, Gebrewold A, Ising H, Gunther T (1984) Magnesium deficiency and hypertension: Correlation between magnesium-deficient diets and microcirculatory changes in situ. Science 223: 1315-1317.
15. Altura BM, Altura BT, Gebrewold A, Gunther T, Ising H (1992) Noise-induced hypertension and magnesium: relationship to microcirculation and Ca. J Appl Physiol 72: 194-202.
16. Altura BM, Shah NC, Shah GJ, Zhang A, Li W, et al. (2012) Short-term magnesium deficiency upregulates ceramide synthase in cardiovascular tissues and cells: crosstalk among cytokines, Mg²⁺, NF-kB and de novo ceramide. Am J Physiol Heart Circ Physiol 302: H319-H332.
17. Altura BM, Shah NC, Shah GJ, Zhang A, Li W, et al. (2014) Short-term Mg deficiency upregulates protein kinase C isoforms in cardiovascular tissues and cells: relation to NF-kB, cytokines, ceramide salvage sphingolipid pathway and PKC-zeta: hypothesis and review. Int J Clin Exp Med 6: 1-21.
18. Weglicki WB (2012) Hypomagnesemia and inflammation. Annu Rev Nutr 32: 55-71.
19. Altura BM, Gebrewold A, Zhang A, Altura BT (2003) Low extracellular magnesium ions induces lipid peroxidation and activation of nuclear factor-kB in canine cerebral vascular smooth muscle: possible relation to traumatic brain injury and strokes. Neurosci Lett 341: 189-192.
20. Altura BM, Kostellow AB, Zhang A, Li W, Morrill GA, et al. (2003) Expression of the nuclear factor-kB and proto-oncogenes c-fos and c-jun are induced by low extracellular Mg²⁺ in aortic and cerebral vascular smooth muscle cells: possible links to hypertension, atherogenesis and stroke. Am J Hypertension 16: 701-707.
21. Altura BT, Brust M, Barbour RL, Bloom S, Stempak J, et al. (1990) Magnesium dietary intake modulates blood lipid levels and atherogenesis. PNAS USA 87: 1840-1844.
22. Altura BM, Altura BT (1995) Magnesium and cardiovascular biology: an important link between cardiovascular risk factors and atherogenesis. Cell Mol Biol Res 41: 347-360.
23. Altura BM, Shah NC, Shah GJ, Altura BT (2018) Magnesium deficiency, sphingolipids and telomerase: relevance to atherogenesis, cardiovascular diseases and aging. In Handbook of Famine, Starvation, and Nutrient Deprivation. Springer, Berlin.
24. Altura BM, Altura BT (1995) Magnesium in cardiovascular biology. Scientific Am Science & Med 2(3): 28-37.
25. Altura BM, Altura BT (1996) Magnesium as an extracellular signal in cardiovascular pathobiology. J Jap Soc Magnesium Res 15:17-32.
26. Altura BM, Altura BT (2007) Magnesium: forgotten mineral in cardiovascular biology and atherogenesis. In; New Perspectives in Magnesium Research, Nishizawa N, Morii H, Durlach J, eds. Kluwer, Amsterdam, pp. 239-260.
27. Altura BT, Shirey TL, Young CC, Hiti J, Dell’Orfano K, et al. (1992) A new method for the rapid determination of ionized Mg²⁺ in whole blood, serum and plasma. Methods and Findings in Exp & Clin Pharmacol 14: 297-304.
28. Altura BT, Altura BM (1992) Measurement of ionized magnesium in whole blood, plasma and serum with a new ion-selective electrode in healthy and diseased human subjects. Magnesium Trace Elem 10: 90-98.
29. Altura BT, Shirey TL, Young CC, Dell Orfano K, Altura BM (1992) Characterization and studies of a new ion selective electrode for free extracellular magnesium ions in whole blood, plasma and serum. In: Electrolytes, Blood Gases and Other Clinical Analytes: The Patient, the Measurement, and the Government, Electrolyte, Blood Gas division AACC, DOrazio P, Burritt MF, Sena SF, eds. Omni Press, WI 14: 152-173.
30. Altura BT, Shirey TL, Young CC, Dell Orfano K, Hiti J, et al. (1994) Characterization of a new ion selective electrode for ionized magnesium in whole blood, plasma, serum and aqueous samples. Scand J Clin Lab Invest 54 (suppl 217): 21-36.
31. Altura BM, Altura BT (2016) Importance of ionized magnesium measurements in physiology and medicine and the need for ion-selective electrodes. J Clin Case Studies 1: 1-4.
32. Ross R (1999) Atherosclerosis---An inflammatory disease. New Engl J Med 340(2): 115-126.
33. Majno G, Joris I (2004) Cells, Tissues, and Disease, 2nd Ed. Oxford University Press, New York, USA.
34. Shirai T, Hillhorst M, Harrison DG, Goronzy JJ, Weyland CC (2015) Macrophages in vascular inflammation----From atherosclerosis to vasculitis. Autoimmunity 48(3): 139-151.
35. Morrill GA, Gupta RK, Kostellow AB, Ma GY, Zhang A, et al. (1997) Mg²⁺ modulates membrane lipids in vascular smooth muscle: a link to atherogenesis. FEBS Lett 408: 191-197.
36. Morrill GA, Gupta RK, Kostellow AB, Ma GY, Zhang A, et al. (1998) Mg²⁺ modulates membrane sphingolipids and lipid second messengers in vascular smooth muscle cells. FEBS Lett 440: 167-171.
37. Zheng T, Li W, Wang J, Altura BT, Altura BM (2000) Sphingomyelinase and ceramide analogs induce contraction and rises in [Ca2+]I in canine cerebral vascular muscle. Am J Physiol Heart Circ Physiol 278(5): 1421-1428.
38. Prescott SM, Zimmerman GA, Stafforini DM, McIntyre TM (2000) Platelet-activating factor and related lipid mediators. Annu Rev Biochem 69: 419-445.
39. Zimmerman GA, McIntyre TM, Prescott SM, Stafforini DM (2002) The platelet-activating factor signaling system and its regulation in syndromes of inflammation and thrombosis. Crit Care Med 30(5): 294-301.
40. Montrucchio G, Alloattti G, Canussi G (2000) Role of platelet-activating factor in cardiovascular pathophysiology. Physiol Rev 80(4): 1669-1699.
41. Altura BM, Gebrewold A, Zhang A, Altura BT (2002) Sphingomyelinase and ceramide analogs induce vasoconstriction and leukocyte endothelial interactions in cerebral venules in intact rat brain: insight into mechanisms and possible relation to brain injury and stroke. Brain Res Bull 58: 271-278.
42. Altura BM, Li W, Zhang A, Zheng T, Shah NC, et al. (2016) The expression of platelet-activating factor is induced by low extracellular Mg²⁺ in aortic, cerebral and neonatal coronary vascular smooth muscle; cross-talk with ceramide production, NF-kB and proto-oncogenes: Possible links to atherogenesis and sudden cardiac death in children and infants, and aging; hypothesis, review and viewpoint. Int J Cardiol Res 3(1): 47-67.
43. Cunningham TJ, Medcalf RL, Mathews JD, Muirden KD (1986) Platelet releasing activity in sera of patients with rheumatoid vasculitis. Ann Rheum Dis 45:15-20.
44. Warren J, Mandel DM, Johnson KJ, Ward PA (1989) Evidence for the role of platelet-activating factor in immune complex vasculitis in the rat. J Clin Invest 83: 669-678.